DNA Methylation Machinery Mediates the Bladder's Response to Obstruction

Partial bladder obstruction arises insidiously and compromises quality of life often by perpetuating urinary tract infections, incontinence and kidney failure. Obstruction leads to prolonged over-distension of the bladder, which induces tissue hypoxia and abnormal extracellular matrix (ECM) remodeling that alters bladder smooth muscle cell (BSMC) phenotype. The BSMCs become hypertrophic and proliferative with loss of differentiation and contractility. The persistence of pathology despite de-obstruction in human and animal bladders in vivo, as well as the stable pheno-pathology found in BSMC in vitro, suggests that responses to bladder obstruction are mediated by the microenvironment. We hypothesize that epigenetic mechanisms mediate irreversible BSMC responses to the obstructive environment. In animals, long-term bladder obstruction significantly increased bladder weight and dysregulated gene expressions, neither were completely reversed by de-obstruction. The ECM regulates BSMC phenotype switching in vitro, which is mediated by alterations in the expression as well as the sub-cellular localization of DNA Methyl-Transferase.M.Sc